Efficacy and safety of nab-paclitaxel plus platinum in non-small cell lung cancer: a meta-analysis

Purpose This meta-analysis was exerted in assessing the anticancer efficacy and safety of nab-paclitaxel (nab-P) when combined with platinum compound agents for therapy in patients with non-small cell lung cancer (NSCLC). Method We systematically searched the following seven electronic databases: PubMed, Cochrane Library, Web of Science, Embase, CNKI, Wan Fang, and China Science and Technology Journal Data. Randomized comparative clinical [randomized controlled clinical trial (RCT)] studies on nab-P plus platinum and carboplatin or cisplatin in combination with conventional chemotherapy agents or traditional paclitaxel were searched. Results A total of 19 RCT studies involving 6,011 patients were analyzed. The primary outcome includes the overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). The secondary outcome includes adverse events (AEs). Nab-P combined with platinum (carboplatin/cisplatin) had a better ORR [odds ratio (OR) = 1.66, 95% confidence interval (CI) (1.34, 2.05), p < 0.001] and improved PFS [hazard ratio (HR) = 0.84, 95% CI: (0.74, 0.94), p = 0.01] and OS [HR = 0.86, 95% CI: (0.78, 0.96), p = 0.008] in NSCLC patients. ORR [OR = 2.18, 95% CI: (1.07, 4.43)], PFS [HR = 0.62, 95% CI: (0.40, 0.97)], and OS [HR = 0.63, 95% CI: (0.49, 0.81)] were significantly improved among patients aged >70 years, and ORR [OR = 1.80, 95% CI: (1.20, 2.70)] and PFS [HR = 0.74, 95% CI: (0.56, 0.97)] were significantly elevated with SCC rate ≥65% in NSCLC patients (all p > 0.05). Among the adverse effects, the prevalence of neutropenia, neuralgia, and arthralgia/myalgia (≥ grade 3) compared to that of the control group. On the other hand, the prevalence of anemia and thrombocytopenia was higher in the nab-P plus platinum (carboplatin/cisplatin) compared to that of controls. It is worth noting that fatigue did not show statistical significance. Conclusion Nab-P in combination with carboplatin/cisplatin regimen improves efficacy and tolerability in patients with NSCLC. Systematic review registration http://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022288499.


. Introduction
Lung cancer, one of the most common cancers, ranked second in new cancer cases (11.4%, 2,206,771) and first in new deaths (18.0%, 1,796,144) in 2020 (1). Based on the cellular origin, lung cancer can be classified into two major categories, namely, small cell type and non-small cell type (2), with non-small cell lung cancer (NSCLC) constituting ∼85% of the lung cancer (3). NSCLC is categorized into three subtypes, namely, lung adenocarcinoma, squamous cell lung cancer, and large cell carcinoma (4). NSCLC patients with a survival rate of 5 years are only ∼15%, as the majority of patients with NSCLC are unresectable or metastatic at diagnosis (5) and are unsuitable for excision surgery, but they instead ought to undergo aggressive systemic therapy (consisting of chemotherapy, targeted therapy, or a combination of both) to achieve a good benefit. Nowadays, nab-P plus platinum compounds have been recommended as chemotherapy regimens to cure advanced NSCLC (6,7).
Nab-P, a paclitaxel of solvent micelles-free, was revealed superior response rates and tolerability than solvent-based paclitaxel treatment regimens with patients in NSCLC and MBC (8). Albumin, as a natural transport carrier, is a general carrier for drug delivery into tumors due to features of abundance in blood and long half-life (9), with high accumulation in tumor tissues. It seems that promoting albumin binding to albuminspecific receptor mediated transport mechanisms to access tumors by enhanced permeation and retention (EPR) effect (10,11). Thus, nab-P could reach the tumor microenvironment more effectively and accumulate in the tumor. In the study (10), nab-paclitaxel (nab-P) and sb-paclitaxel were radiolabeling then quantified the paclitaxel reaching tumors presenting that tumors have absorbed one-third more nab-P. This likewise illustrated that nab-P takes advantage of albumin mechanisms so that it could reach tumors more advantageously and consequently inhibit tumor growth. The NCCN guidelines suggest that albumin-bound paclitaxel combined with platinum was used as standard treatment (6). A stage III/IV squamous NSCLC, clinical trial, indicated the beneficial effects of nab-P plus platinum compounds as the firstline chemotherapy for patients who have commonly used advanced NSCLC (12). In addition, in a clinical trial, among patients with NSCLC aged ≥60 years, nab-P plus carboplatin (nab-P + C) considerably increased overall response rate (ORR; 34 vs. 25.6%) and prolonged overall survival (OS; 13.8 vs. 11.0 months) compared with solvent-based paclitaxel in combination with carboplatin; however, it did not significantly show progression-free survival (PFS; 6.9 vs. 5.7 months). Among adverse effects, the maximum number of neutropenia incidence (≥ grade 3) was lower in nab-P + C than sb-paclitaxel plus carboplatin (134 vs. 152) and the incidence of anemia (74 vs. 16) or thrombocytopenia (45 vs. 20) is slightly higher in nab-P + C (13). However, single studies generally have heterogeneity and risk of bias, and the accuracy of study results may be limited. We, therefore, systematically assessed the . /fmed. .
. Materials and methods

. . Literature search
We searched, using the keywords "Carcinoma, Non-Small-Cell Lung" and "Albumin-Bound Paclitaxel, " PubMed, Cochrane Library, Web of Science, Embase, CNKI, Wan Fang, and China Science and Technology Journal Data databases from 1 January 2012 until the end of May 2022.

. . Eligibility criteria
The inclusion criteria were as follows: (1) the study category was a clinical trial or prospective study; (2) the study was a randomized controlled trial; (3) the study population was patients with histologically or pathologically confirmed NSCLC; (4) the study involved different intervention drugs, using albumin-bound paclitaxel combined with platinum chemotherapy in the trial group and platinum combined with other drugs in the control group or traditional paclitaxel; and (5) outcomes reported post-intervention as ORR, PFS, OS, adverse event (AE) outcomes grade ≥3.
The exclusion criteria were as follows: (1) articles in which the required information was not available and (2) article types, namely, retrospective study, case report, meta-analysis, review, and animal studies.

. . Research quality assessment
We checked the quality of each included study using Cochrane and evaluated the risk of bias using Review Manager 5.4.

. . . Data extraction
After screening by two authors, the information extracted for the selected articles included the first author's name and year of publication; patient number, gender, and age median; squamous cell carcinoma (SCC)/non-SCC; and style of study (Table 1). Table 2 includes treatment regimen per group; number of samples studied;

FIGURE
The flow diagram of the study selection process. nab-P + C, nab-p combined with carboplatin; nab-P + Cis, nab-p combined with cisplatin.

. . . Statistical analysis
Meta-analysis was compared with the pooled results of hazard ratio (HR) with 95% confidence interval (CI) of the primary outcome (ORR, OS, and PFS) and the number of AEs (≥ grade 3), using the STATA14.0 software. The heterogeneity present in the studies was estimated by Cochrane's Q-test and I 2 statistics test, and the data were analyzed to use a random-effects model if the I 2 was >50% or heterogeneity p was <0.1. In the opposite case, a fixed-effects model was used. Moreover, p-values > 0.05 were not recognized as statistically significant. A sensitivity analysis was generated using Comprehensive Meta-Analysis V3 to judge the stability of the pooled results. Publication bias was examined by contour-enhanced funnel plots and Begg's and Egger's tests.
Publication bias existed when there was asymmetry in the funnel plot or p < 0.05 in Begg's and Egger's tests.

. . . Evidence grading
The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guideline suggested a tool that estimated the evidence quality for 10 outcomes (ORR, PFS, OS, neutropenia, anemia, thrombocytopenia, neuropathic pain, gastrointestinal reactions, joint myalgia, and fatigue).

. Results
We searched 1,044 studies after screening the electronic databases. Excluding 1,026 studies based on the titles and abstracts, we finally obtained 18 studies for random trial studies that conformed to the inclusion and exclusion criteria ( Figure 1). An included original study (13) grouped the data pooled according to age and was considered as two articles at inclusion. Therefore, the total number of included studies was 19. The total sample size of meta-analysis was 6,011 cases. The general characteristics of the patients are presented in Table 1. To enable research, we aggregated the drug interventions referred to in the included reports as shown in Table 2.
The methodological quality graph and summary of all included studies are shown in Figures 2A, B. The included articles do not address the allocation concealment. Furthermore, none of the studies had or illustrated double-blind procedures.

. . . Security analysis
The results of treatment associated AEs grade ≥ 3 are shown in Table 4 and Figure 6. AEs can be divided into hematologic and nonhematologic AEs, with neutropenia [control arms vs. experiment arms (51%: 47%)] being the most common as shown in Table 5.

. . . Meta-regression analysis
The aim of this analysis was to appraise the correlation by dose and duration of the intervention (months) of nab-P + C/Cis with ORR, PFS, and OS. According to the results, no linear correlation was observed for the absolute changes in these factors with the intervention dose and intervention duration (Figure 7). Based on the data of intervention, the duration of OS was consistent across the 11 studies, and thus no results were available in OS.

. . . Sensitivity analyses
We used the sensitivity analysis to evaluate the outcomes. These outcomes were presented with no significant modifications of ORR, PFS, OS, and AES ( Figure 8) after deleting the studies one by one, suggesting that the valid results of therapeutic response were relatively stable in patients under nab-P + C/Cis treatment.

. . . Assessment of publication bias
Contour-enhanced funnel plots were performed to appraise the results of potential publication bias. Conventional assignment criteria at the statistical significance level (p < 0.01, < 0.05, and < 0.1) were added to the funnel plot     Doc  60  75  37  2  10  1  1  0  0  0  3  2  12  3 Event (n, %) --  for distinguishing the detailed causes of publication bias. Figure 9 shows that there were asymmetrical, with many missing studies that fall in the areas of high statistical significance. Using Begg's and Egger's tests for further assessments, the results obtained were quantifiable, indicating the absence of potential publication bias. More details are presented in Table 6. In total, this study illustrated that the asymmetry may occur as a result of reasons other than publication bias.

. . . Quality of evidence
The quality of the evidence table ( Figure 10) was assessed for each outcome. Neutropenia presented high evidence. ORR, PFS, OS, neuropathy, gastrointestinal reactions, and arthralgia/myalgia outcomes had moderate certainty. Anemia, thrombocytopenia, and fatigue presented with low certainty.

. Discussion
The meta-analysis included 19 randomized clinical studies with 6,011 participants and presented the effectiveness of nab-P combined with carboplatin/cisplatin interventions in achieving improved ORR, prolonged PFS and OS, and declined AEs. These studies revealed that the combined regiments increase anticancer efficacy in patients with NSCLC and reasonable AEs occurrence which is generally acceptable.
Depending on the results, nab-P combined with platinum (carboplatin/cisplatin) elevated ORR     NSCLC between nab-P + C and nab-P + Cis. The lack of directly comparable clinical trials prevents us from determining which chemotherapy regimen is more effective. In an analysis of subgroups according to median age, the nab-P + C/Cis regimen significantly increased ORR and extended the duration of PFS and OS in the age > 70 years arm. Furthermore, by subgroup analysis depending on the SCC rate, the nab-P + C/Cis regimen was found to enhance ORR and growth in PFS greater in the SCC rate ≥ 65% arm. This implies that nab-P + C/Cis chemotherapy regimens may benefit more dramatically in older patients with NSCLC and patients with squamous cell carcinoma. AEs can be separated into hematologic and non-hematologic events, based on the occurrence of neutropenia with the highest rate. Among the adverse results (grade ≥ 3) that showed in terms of hematological toxicities, when compared to carboplatin or cisplatin in combination with conventional chemotherapy agents or traditional paclitaxel, anemia [ In a present meta-analysis of the efficacy and safety of nab-P in combination with carboplatin for NSCLC, Tan et al. (31) demonstrated that, in comparison to control, nab-P + C improved ORR and extended PFS and OS. In the area of AEs, nab-P + C raised the incidence of anemia (grade ≥ 3) and diminished the risk of grade ≥ 3 neuropathy and arthralgia. There was no previous meta-analysis of nab-P + Cis intervention in NSCLC, but a review analysis (32) has reported an aggressive effect of nab-P + Cis intervention in NSCLC, with a tendency to obtain a higher ORR and improved PFS and OS. nab-P + Cis was more well-tolerated as illustrated in the trial by Hattori et al. (33). Our findings were similar to those that have been reported.
Patients significantly benefit in terms of ORR after nab-P + C/Cis chemotherapy (12, 17). The mechanism of action of albumin combined with carboplatin/cisplatin for intervention against NSCLC may be to utilize albumin features for increasing the antitumor role of the drug. Tumors may be fed by albumin as a nutritive substance in the tumor microenvironment and it possibly promotes tumor growth (34). Nab-P, an albumin-bound drug, leverages these mechanisms to enhance the delivery specifically to tumors that an affinity for albumin. The gp60 receptorspecific endothelial cells activate transmembrane transport, and albumin accumulates in the tumor environment by the EPR effect to reach tumors (8,10,11). The studies show that the coadministration of albumin-bound paclitaxel with gemcitabine enhances the gemcitabine levels in tumors of a mouse model of pancreatic cancer (35, 36). This supports the possibility that albumin-bound paclitaxel could increase the level of combined drugs reaching the tumor, but more research data are required to support this.
This meta-analysis included clinical studies of nab-P in combination with cisplatin, and it had a higher total sample size. Second, contour-enhanced funnel plots and Begg's and Egger's tests demonstrated that no evidence of publication bias was observed in this study. Besides, outcome quality was graded according to grade guidelines, and correlations for ORR, PFS, and OS with intervention dose and intervention duration were estimated using a regression analysis. However, there are several limitations to this analysis. First, the study shows considerable heterogeneity with respect to ORR, PFS, OS, neutropenia, anemia, and thrombocytopenia. Although using the subgroup analysis and a random-effects model, there is no way to decrease heterogeneity. In the second place, with two of the accepted articles, no HR was provided and calculated using Kaplan-Meier survival curves, which may cause a potential risk of bias (22,26). Finally, most of the studies of nab-P + Cis in terms of primary data are unavailable or unable to calculate HR for PFS and OS, and AEs are not graded.

. Conclusion
In general, this meta-analysis demonstrates that nab-P combined with carboplatin/cisplatin in patients with NSCLC could significantly increase ORR and prolong PFS and OS. However, PFS and OS do not show any particularly visible benefit; therefore, a greater number of studies will be demanded to explore further. Based on the efficacy and tolerability of nab-P combined with carboplatin/cisplatin, it may provide an economically disadvantaged patient with an affordable treatment option.

Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

Author contributions
TT and SL were responsible for drafting the initial text and making equivalent revisions. WH and TY conducted data analysis for the revised manuscript, while QZ and XZ extracted and analyzed data from the original manuscript. XC, XZ, and TX played significant roles in the conceptualization and design of the study. All authors contributed to the article and approved the submitted version.